ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.1714C>T (p.Arg572Ter) (rs137852761)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130661 SCV000185547 pathogenic Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing The p.R572* pathogenic mutation (also known as c.1714C>T), located in coding exon 14 of the MRE11A gene, results from a C to T substitution at nucleotide position 1714. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation was reported in two siblings with ataxia telangiectasia-like disorder (ATLD) and was found to result in nonsense-mediated decay (Pitts SA et al. Hum. Mol. Genet. 2001 May;10:1155-62). In addition, two Italian siblings with ATLD were found to be compound heterozygous for this mutation, and their clinical course is well documented (Delia D et al. Hum. Mol. Genet. 2004 Sep;13:2155-63; Palmeri S et al. Cerebellum. 2013 Aug;12:596-9). Of note, this alteration is also designated as R571X in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000791361 SCV000764140 pathogenic Ataxia-telangiectasia-like disorder 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg572*) in the MRE11 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs137852761, ExAC 0.01%). This variant has been reported in the literature in individuals affected with ataxia-telangiectasia-like disorder (PMID: 11371508, 15269180). This variant is also known as p.R571X in the literature. ClinVar contains an entry for this variant (Variation ID: 8784). Experimental studies have shown that this nonsense change leads to nonsense mediated decay and lack of expression of the MRE11 protein, leading to increased radiosensitivity in compound heterozygous patient cells (PMID: 11371508, 15269180). Loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000009329 SCV000915562 likely pathogenic Ataxia-telangiectasia-like disorder 1 2018-10-22 criteria provided, single submitter clinical testing The MRE11A c.1714C>T (p.Arg572Ter) variant is a stop-gained variant predicted to cause a premature truncation of the protein. The p.Arg572Ter variant has been reported in at least two studies in which it is found in a compound heterozygous state in two pairs of siblings from two families with ataxia-telangiectasia-like disorder (Pitts et al. 2001; Delia et al. 2004; Federighi et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Arg572Ter variant protein could not be detected in proband cells due to destabilisation of the variant by nonsense-mediated mRNA decay. In addition, functional assays in patient lymphoblastoid cell lines demonstrated that the p.Arg572Ter variant protein resulted in a defective MRN complex and exhibited enhanced radio sensitivity in colony survival assays (Pitts et al. 2001; Delia et al. 2004). Based on the evidence, the p.Arg572Ter variant is classified as likely pathogenic for ataxia-telangiectasia-like disorder. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000791361 SCV001362361 pathogenic Ataxia-telangiectasia-like disorder 2019-09-06 criteria provided, single submitter clinical testing Variant summary: MRE11A c.1714C>T (p.Arg572X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 6e-05 in 251278 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MRE11A causing Ataxia Telangiectasia-like Disorder (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1714C>T has been reported in the literature in individuals affected with Ataxia Telangiectasia-like Disorder (Delia_2004, Pitts_2001), along with individuals affected with pancreatic cancer (Hu_2018) and breast cancer (Lolas Hamameh_2017). These data indicate that the variant is likely to be associated with disease. In addition, functional studies utilizing samples from compound heterozygote patients found the nonsense change to cause NMD leading to lack of MRE11A protein expression and causing an increased radiosensitivity (Delia_2004). Four ClinVar submissions (evaluation after 2014) cite the variant three times as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001531123 SCV001746099 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
OMIM RCV000009329 SCV000029547 pathogenic Ataxia-telangiectasia-like disorder 1 2001-05-15 no assertion criteria provided literature only

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